Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by multifocal regions of inflammation and myelin destruction. Typically, MS runs a protracted clinical course lasting over several decades with episodes of exacerbation followed by variable periods of remission. Available evidence indicates that the cause of MS is multifactorial and includes the genetic background of the individual as well as environmental influences e.g., viral infection. The development of animal models in which the clinical and histologic pathology is similar to that observed in the majority of MS patients is imperative in order to attempt to better understand the underlying pathological mechanisms contributing to MS. Viral models of demyelination are important tools for studying the pathogenesis of disease. Persistent infection of mice with the neurotropic JHM strain of mouse hepatitis virus (MHV) is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS). Combined with the fact that an environmental agent such as a virus is considered to be a contributing cause of MS, the MHV system offers an excellent model in which to study both the underlying immunopathological mechanisms that may drive demyelination in MS patients as well as novel therapeutic methods for promoting remyelination. Stem cells offer an exciting new avenue for treatment of many autoimmune diseases including MS. We now have determined that intraspinal transplantation of human pluripotent-derived neural precursor cells (hNPCs) into MHV-infected mice with established demyelination results in sustained clinical improvement that is associated with reduced neuroinflammation and remyelination. Our findings indicate that transplanted hNPCs are rejected indicating that these cells are capable of modulating the microenvironment that allow for prolonged clinical recovery. Preliminary results indicate that hNPC-mediated recovery is associated with the emergence of regulatory T cells that presumably dampen neuroinflammation as well as activation/maturation of endogenous oligodendrocyte progenitor cells that likely contribute to remyelination. This application will interrogate the underlying mechanisms by which hNPCs contribute to repair and recovery of motor skills.